MACROCYCLIC COMPOUNDS AND THEIR USE IN THE TREATMENT OF DISEASE Russian patent published in 2023 - IPC C07D515/14 C07D513/14 C07D498/14 A61K31/4365 A61P11/00 

FIELD: medical chemistry.

SUBSTANCE: compound of formula (I-c) or formula (I-d) or a pharmaceutically acceptable salt thereof, where X_1a is N; X_2a is N; X_3a is CH or N; X₄ is or -O-, where * denotes the point of attachment to L₂; L₂ represents -(CR⁴R⁵)_n-, -O(CR⁴R⁵)_n-*, -NR⁷(CR⁴R⁵)_n-**, -(CR⁴R⁵)_nO(CR⁶R¹⁰)_p-**, -(CR⁴R⁵)_n(CR⁶R¹⁸)-**, -(CR⁴R⁵)_n(CR⁸R⁹)_p(CR⁴R⁵)_m-, -(CR⁴R⁵)_pNR⁷(CR⁶R¹⁰)_n-**, -(CR⁴R⁵)_nO)_t(CR⁶R¹⁰)_p-** or -O-C₃-C₈cycloalkylene-**, where ** denotes the point of attachment to X₄; each ¹ is independently selected from H, halogen, halogen-substituted C₁-C₆alkyl, C₁-C₆alkyl, deuterium-substituted C₁-C₆alkyl, nitrile, hydroxyl, C_1-6alkoxy, and halogen-substituted C_1-6alkoxy; each R² is independently selected from H, halogen, nitrile, hydroxyl, halogen-substituted C_1-6alkyl, C_1-6alkyl, deuterium-substituted C₁-C₆alkyl, hydroxy-substituted C₁-C₆alkyl, C_1-6alkoxy and halogen-substituted C_1-6alkoxy; R³ represents H, -C_1-6alkyl, -(CR¹¹R¹²)_yR¹⁶, -(CR¹¹R¹²)_yC(=O)OR¹³, -((CR¹¹R¹²)_yO(CR¹⁴R¹⁵)_zC(=O)OR¹³, -((CR¹¹R¹²)_yO(CR¹⁴R¹⁵)_zOR¹³, -(CR¹¹R¹²)_yC(=O)R¹³, -(CR¹¹R¹²)_yOR¹³, -(CR¹¹R¹²)_y(CR⁸R⁹)_z C(=O)OR¹³, -(CR¹¹R¹²)_y(CR⁸R⁹)_zOR¹³, -(CR¹¹R¹²)_y(CR⁸R⁹)_z(CR¹⁴R¹⁵)_qOR¹³, -(CR¹¹R¹²)_yNR¹⁰(CR¹⁴R¹⁵)_qC(=O)OR¹³, -(CR¹¹R¹²)_yNR¹³R¹⁴, -(CR¹¹R¹²)_yR²⁰, -((CR¹¹R¹²)_yO)_q(CR¹⁴R¹⁵)_zC(=O)OR¹³, -((CR¹¹R¹²)_yO)_q(CR¹⁴R¹⁵)_zOR¹³, or ; each R⁴ is independently selected from H, D, deuterium-substituted C₁-C₆alkyl and C_1-6alkyl; each R⁵ is independently selected from H, D, deuterium-substituted C₁-C₆alkyl and C_1-6alkyl; each R⁶ independently is independently selected from H, D, deuterium-substituted C₁-C₆alkyl and C_1-6alkyl; each R⁷ is independently selected from H and C_1-6alkyl; each R⁸ and R⁹ are independently selected from H, D, deuterium-substituted C₁-C₆alkyl, C_1-6alkyl and -OH; or R⁸ and R⁹ together with the carbon atom in CR⁸R⁹, they form C_3-8cycloalkyl; each R¹⁰ is independently selected from H, D and C_1-6alkyl; each R¹¹ is independently selected from H, D and C_1-6alkyl; each R¹² is independently selected from H, D, deuterium-substituted C₁-C₆alkyl and C_1-6alkyl; each R¹³ is independently selected from selected from H and C_1-6alkyl; each R¹⁴ is independently selected from H, D, deuterium-substituted C₁-C₆alkyl and C_1-6alkyl; each R¹⁵ is independently selected from H, D, deuterium-substituted C₁-C₆alkyl and C_1-6alkyl; R¹⁶ is a 4-6-membered heterocycloalkyl comprising 1 or 2 ring atoms independently selected from N, O and S, where the indicated 4-6-membered heterocycloalkyl is unsubstituted or replaced by 1 or 2 groups of R¹⁷; each R¹⁷ is independently selected from C_1-6alkyl and hydroxyl; R¹⁸ is H, C_1-6alkyl, -C(R⁴R⁵)_mOR¹⁹ or -(CH₂)_mC(=O)OR¹⁹; each R¹⁹ is independently selected from H and C_1-6alkyl; R²⁰ is

or ; each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each p is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each t is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each w is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each y is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; each z is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and each q is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

EFFECT: new compounds have been obtained that can be used in medicine in the treatment of cystic fibrosis and CFTR-related disorders.

9 cl, 1 tbl, 133 ex